Sufugolix

Sufugolix (INN, BAN) (developmental code name TAK-013) is a non-peptide, orally-active, selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (IC50 = 0.1 and 0.06 nM for affinity and in vitro inhibition, respectively).[1] It was under development by Takeda for the treatment of endometriosis and uterine leiomyoma and reached phase II clinical trials for both of these indications, but was subsequently discontinued.[2][3] It seems to have been supplanted by relugolix (TAK-385), which is also under development by Takeda for the treatment of these conditions and has a more favorable drug profile (including reduced cytochrome P450 inhibition and improved in vivo GnRHR antagonistic activity) in comparison.[4]

Sufugolix
Clinical data
Other namesTAK-013
Routes of
administration		By mouth
Drug classGnRH modulator; GnRH antagonist; Antigonadotropin
ATC code
  • None
Identifiers
IUPAC name
  • 1-[4-[5-[[benzyl(methyl)amino]methyl]-1-[(2,6-difluorophenyl)methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC36H31F2N5O4S
Molar mass667.73 g·mol−1
3D model (JSmol)
SMILES
  • CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
InChI
  • InChI=1S/C36H31F2N5O4S/c1-41(20-23-10-5-3-6-11-23)21-28-31-33(44)43(26-12-7-4-8-13-26)36(46)42(22-27-29(37)14-9-15-30(27)38)34(31)48-32(28)24-16-18-25(19-17-24)39-35(45)40-47-2/h3-19H,20-22H2,1-2H3,(H2,39,40,45)
  • Key:UCQSBGOFELXYIN-UHFFFAOYSA-N

Oral administration of sufugolix at a dose of 30 mg/kg to castrated male cynomolgus monkeys resulted in nearly complete suppression of luteinizing hormone levels.[1] The duration of action was more than 24 hours, indicating a long elimination half-life of the drug.[1] The suppressive effects of sufugolix on gonadotropin and sex hormone levels are rapidly reversible with discontinuation.[5]

Unlike various other GnRHR antagonists, sufugolix has been elucidated to be a non-competitive or insurmountable/trapping antagonist of the GnRHR rather than a competitive antagonist.[6][7]

See also
  • Gonadotropin-releasing hormone receptor § Antagonists

References
  1. Sasaki S, Cho N, Nara Y, Harada M, Endo S, Suzuki N, Furuya S, Fujino M (2003). "Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor". J. Med. Chem. 46 (1): 113–24. doi:10.1021/jm020180i. PMID 12502365.
  2. Lanier, Marion C.; Feher, Miklos; Ashweek, Neil J.; Loweth, Colin J.; Rueter, Jaimie K.; Slee, Deborah H.; Williams, John P.; Zhu, Yun-Fei; Sullivan, Susan K.; Brown, Michael S. (2007). "Selection, synthesis, and structure–activity relationship of tetrahydropyrido[4,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists". Bioorganic & Medicinal Chemistry. 15 (16): 5590–5603. doi:10.1016/j.bmc.2007.05.029. ISSN 0968-0896. PMID 17561404.
  3. "Sufugolix - Takeda - AdisInsight".
  4. Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T (2011). "Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor". J. Med. Chem. 54 (14): 4998–5012. doi:10.1021/jm200216q. PMID 21657270.
  5. Hara T, Araki H, Kusaka M, Harada M, Cho N, Suzuki N, Furuya S, Fujino M (2003). "Suppression of a pituitary-ovarian axis by chronic oral administration of a novel nonpeptide gonadotropin-releasing hormone antagonist, TAK-013, in cynomolgus monkeys". J. Clin. Endocrinol. Metab. 88 (4): 1697–704. doi:10.1210/jc.2002-021065. PMID 12679460.
  6. Kohout TA, Xie Q, Reijmers S, Finn KJ, Guo Z, Zhu YF, Struthers RS (2007). "Trapping of a nonpeptide ligand by the extracellular domains of the gonadotropin-releasing hormone receptor results in insurmountable antagonism". Mol. Pharmacol. 72 (2): 238–47. doi:10.1124/mol.107.035535. PMID 17409285. S2CID 23980337.
  7. Szkudlinski MW (2007). "Challenges and opportunities of trapping ligands". Mol. Pharmacol. 72 (2): 231–4. doi:10.1124/mol.107.038208. PMID 17522183. S2CID 25807899.



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